Mps1 inhibitors synergise with low doses of taxanes in promoting tumour cell death by enhancement of errors in cell division

Background Chromosomal instability (CIN) is a common trait of cancer characterised by the continuous gain and loss of chromosomes during mitosis. Excessive levels of CIN can suppress tumour growth, providing a possible therapeutic strategy. The Mps1/TTK kinase has been one of the prime targets to ex...

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Bibliographic Details
Published in:British journal of cancer 2018-06, Vol.118 (12), p.1586-1595
Main Authors: Maia, Ana Rita R., Linder, Simon, Song, Ji-Ying, Vaarting, Chantal, Boon, Ute, Pritchard, Colin E. J., Velds, Arno, Huijbers, Ivo J., van Tellingen, Olaf, Jonkers, Jos, Medema, René H.
Format: Article
Language:English
Subjects:
631/80/641
692/4028/67/1059
Apoptosis
Biomedical and Life Sciences
Biomedicine
BRCA1 protein
Breast cancer
Cancer
Cancer Research
Cell death
Cell division
Chromosomes
Copy number
Drug Resistance
Epidemiology
Genomic instability
Histopathology
Inhibitors
Kinases
Mice
Mitosis
Molecular Medicine
Oncology
p53 Protein
Taxanes
Tumors
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Summary:Background Chromosomal instability (CIN) is a common trait of cancer characterised by the continuous gain and loss of chromosomes during mitosis. Excessive levels of CIN can suppress tumour growth, providing a possible therapeutic strategy. The Mps1/TTK kinase has been one of the prime targets to explore this concept, and indeed Mps1 inhibitors synergise with the spindle poison docetaxel in inhibiting the growth of tumours in mice. Methods To investigate how the combination of docetaxel and a Mps1 inhibitor (Cpd-5) promote tumour cell death, we treated mice transplanted with BRCA1 −/− ;TP53 −/− mammary tumours with docetaxel and/or Cpd-5. The tumours were analysed regarding their histopathology, chromosome segregation errors, copy number variations and cell death to understand the mechanism of action of the drug combination. Results The enhanced efficacy of combining an Mps1 inhibitor with clinically relevant doses of docetaxel is associated with an increase in multipolar anaphases, aberrant nuclear morphologies and cell death. Tumours treated with docetaxel and Cpd-5 displayed more genomic deviations, indicating that chromosome stability is affected mostly in the combinatorial treatment. Conclusions Our study shows that the synergy between taxanes and Mps1 inhibitors depends on increased errors in cell division, allowing further optimisation of this treatment regimen for cancer therapy.
ISSN:0007-0920
1532-1827
DOI:10.1038/s41416-018-0081-2